Delayed-type hypersensitivity (DTH) reactions are antigen-specific cell-mediated immune responses that can mediate harmful (e.g., allergic dermatitis and autoimmunity) aspects of immune function. The immune reaction is characterized by swelling at the site of challenge and by an infiltration of monocytes/macrophages and lymphocytes into the epidermis and dermis. Type IV or DTH, is most seriously manifested when antigens (for example those of tubercle bacilli) are trapped in a macrophage and cannot be cleared. T cells are then stimulated to elaborate lymphokines which mediate a range of inflammatory responses. Other aspects of DTH reactions are seen in graft rejection and allergic contact dermatitis. DTH is used as a general category to describe all those hypersensitivity reactions which take more than 12 hours to develop, and which involve cell-mediated immune reactions rather than humoral immune reactions. Whereas allergic reactions occur within seconds and minutes and immune complex reactions occur within several hours to one day, DTH reactions peak at 2 to 3 days.
Unlike other forms of hypersensitivity, type IV hypersensitivity cannot be transferred from one animal to another by serum, but can be transferred by T cells (TH1 cells in mice). In humans, transfer from a sensitized to a non-sensitized individual can be also achieved only by T lymphocytes and, interestingly, by a low molecular weight material extracted from them (transfer factor). DTH is associated with T cell protective immunity but does not necessarily run parallel with it—there is not always a complete correlation between delayed hypersensitivity and protective immunity. The T cells necessary for producing the delayed response are cells which have become specifically sensitized to the particular antigen by a previous encounter, and they act by recruiting other cell types to the site of the reaction.
Three types of delayed hypersensitivity reaction are recognized: Contact hypersensitivity and tuberculin-type hypersensitivity both occur within 72 hours of antigen challenge, whereas granulomatous reactions develop over a period of weeks. The granulomas are formed by the aggregation and proliferation of macrophages, and may persist for weeks. This reaction is, in terms of its clinical consequences, by far the most serious type of DTH response. The position is complicated because these different types of reaction may overlap, or occur sequentially following a single antigenic challenge.
The DTH reactions are likely important for host defense against intracellular parasites such as tuberculosis and certain viruses and are prevalent in certain disease such as sarcoidosis, Wegener's granulomatosis, and polymyositis. In some diseases, such as chronic granulomatous disease of childhood, granuloma formation can lead to obstruction of vital structures such as the esophagus or ureters.
Contact hypersensitivity, or contact dermatitis, is a T cell-mediated cutaneous immune/inflammatory reaction to haptens. Typical manifestations of contact dermatitis include, but are not limited to, rashes, dermatoses, and skin eruptions, which can be treated topically to improve or favorably alter the disease condition. Such rashes, dermatoses or skin eruptions include acute, inflammatory reactions of the skin caused by an allergic or irritant reaction (such as that caused by, for example, poison ivy, poison oak or poison sumac, or other forms of allergic or irritant contact dermatitis), other forms of eczema, lichen simplex chronicus, rashes, dermatoses or skin eruptions of a chronic nature (such as, for example, seborrheic dermatitis, psoriasis, atopic dermatitis) or caused by infection, irritation or aggravation of another condition such as occurs with acne, and other rashes, dermatoses or skin eruptions.
Contact dermatitis may be produced by primary irritants or allergic sensitizes. Irritant contact dermatitis is a nonallergic reaction of the skin caused by exposure to irritating substances. Most primary irritants are chemical substances, although physical and biologic (infectious) agents may produce the same reaction. Irritants account for 80% of occupational contact dermatitis and also cause the most frequent type of non-industrial contact reaction. Allergic contact dermatitis is a manifestation of delayed hypersensitivity and results from the exposure of sensitized individuals to contact allergens. Poison ivy and poison oak induce sensitization in more than 70% of the population, thereby causing allergic contact dermatitis (Arndt, Kenneth A., Manual of Dermatologic Therapeutics, 5th edition, 1995, Little, Brown and Co., page 49).
Irritants may cause an inelastic and stiff-feeling skin, discomfort due to dryness, pruritus secondary to inflammation, and pain due to fissures, blisters, and ulcers. Mild irritants produce erythema, microvesiculation, and oozing that may be indistinguishable from allergic contact dermatitis. Chronic exposure to mild irritants or allergens results in dry, thickened, and fissured skin. Strong irritants cause blistering, erosion, and ulcers of the skin. Allergic contact dermatitis, in its mild form, is similar in appearance to the irritant eruption. A more typical allergic contact reaction may consist of grouped or linear tense vesicles and blisters. If involvement is severe there may be marked edema, particularly of the face and in the periorbital and genital areas.
Generally, eczematous dermatitides include a group of diseases which present with a common morphology: erythematous and papulovesicular when acute; erythematous and scaling (with or without fissures and lichenification) when chronic. Included under this rubric are atopic dermatitis, contact dermatitis, nummular dermatitis, seborrheic dermatitis and stasis dermatitis.
Atopic dermatitis is a common infantile eczema which affects approximately 10-20% of children in the United States. The disease has a strong association with allergic rhinitis and asthma and occurs in approximately one-third of children with a personal or family history of these disorders. Although IgE antibodies may be elevated in up to 80% of individuals with atopic dermatitis, the skin manifestations do not seem to be a purely IgE-mediated process. The etiology of atopic dermatitis is unknown. Current hypotheses have concentrated on the possibility that an aberrant T cell response, perhaps to staphylococcal superantigen, results in the activation of TH2 cells.
Clinically, atopic dermatitis has been called the “itch that rashes.” Pruritus is a hallmark of the disease. Infants less than 18 months of age typically present with an acute to subacute dermatitis which may involve the scalp, the face (particularly the cheeks), the posterior neck, the trunk and the extensor aspects of the extremities. After approximately two years of age, most individuals will present with a more chronic, lichenified and scaling form of the disease distributed about the face, neck, trunk and especially the flexural aspects of the extremities (antecubital and popliteal fossae). The reason for the change in distribution of the dermatitis on the extremities is not clear. Individuals with atopic dermatitis are prone to develop secondary infection with staphylococcal organisms, as well as with viruses and fungi. When the disease is flaring, these secondary infections must be excluded.
Contact Dermatitis, also described above, can be broken down into two main areas: irritant contact dermatitis and allergic contact dermatitis.
Irritant contact dermatitis is the direct result of injury to the skin caused by chemical exposure. Irritation can be further subdivided into acute corrosion (caused by a single exposure to strong acids and alkalis), acute irritation (caused by a single exposure to chemicals such as strong solvents and non-corrosive acids and bases), cumulative irritation (the most typical and caused by repeated exposures particularly to surfactants and emulsifiers) and phototoxicity (caused by exposure to irritating chemicals which require light for their activation). The clinical presentation of irritation can therefore vary from the acute onset of a third degree chemical burn (corrosion following phenol exposure) to the chronic scaling and xerotic dermatitis of “dishpan hands.” Because irritant contact dermatitis is a function of the chemical, it will occur in all individuals exposed to this chemical given sufficient exposure times and concentrations. Nonetheless, it is clear that the skin of some individuals is much more irritable than others. The determinants of hyperirritable skin are numerous and include age, genetics, ambient environment, underlying skin disease(s), and concomitant chemical exposure.
Allergic contact dermatitis (ACD) develops following exposure to chemicals to which the individual has previously become sensitized. It is a type IV or delayed-type hypersensitivity reaction of the skin. There are over 3,000 environmental allergens which have been reported to cause this condition. The prevalence of ACD varies with the allergen. Typically, the patient will develop an erythematous, scaling, papulovesicular dermatitis at the sites of contact with the allergen. Longstanding, low grade allergens can create a more subacute to chronic, scaling lichenified dermatitis.
Nummular dermatitis is characterized by its “coin-shaped” lesions. As with other dermatitides, the acute form is papulovesicular whereas the chronic form is scaly and lichenified. Mild to severe pruritus accompanies the disease which most frequently affects men, typically in the sixth decade or beyond. The prevalence of the disease is unknown, but it would appear to be lower than that for most of the other eczemas.
Seborrheic dermatitis is one of the most common cutaneous diseases and affects from 3 to 5% of the population. One proposed etiology is overgrowth of Pityrosporum, a yeast that normally inhabits sebaceous skin (e.g., scalp, eyebrows, central face). The disease has two peaks, one in infancy and the other post-pubertal. Infantile seborrheic dermatitis typically occurs within the first months of life and affects the scalp (“cradle cap”) and intertriginous areas with scales and crust. The skin about the ears and the neck may also be involved. In contrast, seborrheic dermatitis in adults typically involves the scalp, face, neck, mid upper chest and intertriginous zones (axillae, groin, submammary, and in obese patients beneath the pannus). On the face, it particularly concentrates about the eyebrows, nasolabial folds and retroauricular areas.
Stasis dermatitis is an eczematous process of the skin of the lower extremities which results from non-specific inflammation presumably induced by the leakage of serum secondary to venous hypertension. The disease is particularly common over the medial and anterior aspects of the shin and malleolar areas. When significant inflammation occurs, it can be accompanied by a secondary autosensitization dermatitis referred to as an “id.”